Compounds

ABSTRACT

This invention relates to componds of formula I ##STR1## which are useful as PDE IV inhibitors and for treating diseases related thereto.

FIELD OF THE INVENTION

The present invention relates to novel phenylcyclohexan-1-ylcarboxylicacids, pharmaceutical compositions containing these compounds, the useof these compounds in treating allergic and inflammatory diseases and tothe use of these compounds to inhibit the production of Tumor NecrosisFactor (TNF).

BACKGROUND OF THE INVENTION

Bronchial asthma is a complex, multifactorial disease characterized byreversible narrowing of the airway and hyperreactivity of therespiratory tract to external stimuli. Identification of noveltherapeutic agents for asthma is made difficult by the fact thatmultiple mediators are responsible for the development of the disease.Thus, it seems unlikely that eliminating the effects of a singlemediator will have a substantial effect on all components of chronicbronchial asthma.

An alternative to the "mediator approach" is to regulate the activity ofcells responsible for the pathophysiology of asthma. Cyclic AMP (cAMP,adenosine cyclic 3',5'-monophosphate) modulates the activity of most, ifnot all, of the cells that contribute to the pathophysiology ofextrinsic (allergic) asthma. An elevation of cAMP would producebeneficial effects including: (1) airway smooth muscle relaxation, (2)inhibition of mast cell mediator release, (3) suppression of neutrophildegranulation, (4) inhibition of basophil degranulation, and (5)inhibition of monocyte and macrophage activation. Cyclic AMP has beenshown to mediate cellular responses to a wide range of hormones,neurotransmitters and drugs; [Krebs Endocrinology Proceedings of the 4thInternational Congress Excerpta Medica, 17-29, 1973].

One potential means to regulate the activity of cells responsible forthe pathophysiology of asthma is to control the intracellular levels ofcyclic AMP. Cellular cAMP levels are elevated when an appropriateagonist binds to particular cell surface receptors, thereby activatingadenylate cyclase to convert Mg⁺² -ATP to cAMP at an accelerated rate.The principal cellular mechanism for the inactivation of cAMP ishydrolysis of the 3'-phosphodiester bond by one or more of a family ofisozymes referred to as cyclic nucleotide phosphodiesterases (cyclicnucleotide phosphodiesterase hereinafter "PDE"s). Hence, compounds thatactivate adenylate cyclase or inhibit phosphodiesterase should beeffective in suppressing the inappropriate activation of airway smoothmuscle and a wide variety of inflammatory cells.

It has been shown that a distinct PDE isozyme, PDE IV, is responsiblefor cAMP breakdown in airway smooth muscle and inflammatory cells.[Torphy, "Phosphodiesterase Isozymes: Potential Targets for NovelAnti-asthmatic Agents" in New Drugs for Asthma, Barnes, ed. IBCTechnical Services Ltd., 1989]. Research indicates that inhibition ofthis enzyme not only produces airway smooth muscle relaxation, but alsosuppresses degranulation of mast cells, basophils and neutrophils alongwith inhibiting the activation of monocytes and neutrophils. Thebeneficial effects of PDE IV inhibition are markedly potentiated whenadenylate cyclase activity of target cells is elevated by appropriatehormones or autocoids. Thus, PDE IV inhibitors would be effective in theasthmatic lung, where levels of prostaglandin E₂ and prostacyclin (bothactivators of adenylate cyclase) are elevated. PDE IV inhibitors offer aunique approach to the pharmacotherapy of bronchial asthma, and possesssignificant therapeutic advantages over agents currently on the marketThe compounds of this invention have the ability to inhibit PDE IV.

The compounds of this invention also inhibit the production of TNF, aserum glycoprotein. Excessive or unregulated TNF production has beenimplicated in mediating or exacerbating a number of undesirablephysiological conditions, such as diseases , and including rheumatoidarthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis andother arthritic conditions; sepsis, septic shock, endotoxic shock, gramnegative sepsis, toxic shock syndrome, adult respiratory distresssyndrome, cerebral malaria, chronic pulmonary inflammatory disease,silicosis, pulmonary sarcoidosis, bone resorption diseases, reperfusioninjury, graft vs. host reaction, allograft rejections, fever andmyalgias due to infection, such as influenza, cachexia secondary toinfection or malignancy, human acquired immune deficiency syndrome(ADS), cachexia secondary to AIDS, AIDS related complex (ARC), keloidformation, scar tissue formation, Crohn's disease, ulcerative colitis,or pyresis, in addition to a number of autoimmune diseases, such asmultiple sclerosis, autoimmune diabetes and systemic lupuserythematosis.

AIDS results from the infection of T lymphocytes with HumanImmunodeficiency Virus (HIV). At least three types or strains of HIVhave been identified: HIV-1, HIV-2 and HIV-3. As a consequence of HIVinfection, T-cell-mediated immunity is impaired and infected individualsmanifest severe opportunistic infections and/or unusual neoplasms. HIVentry into a T lymphocyte requires prior T lymphocyte activation. Oncean activated T lymphocyte has been infected with HIV, the T lymphocytemust be maintained in an activated state in order to permit HIV geneexpression and/or HIV replication.

Cytokines, including TNF, are implicated in activated T-cell-mediatedHIV protein expression and/or virus replication as playing a role inmaintaining T lymphocyte activation. Therefore, interference withcytokine activity in an HIV-infected individual, such as by inhibitionof TNF production, aids in limiting the maintenance of T cellactivation, and thereby mitigates the progression of HIV infection topreviously uninfected cells. When HIV infection of previously uninfectedcells is diminished, a slowing or elimination of the progression ofimmune dysfunction caused by HIV infection results.

Monocytes, macrophages, and related cells, such as kupffer and glialcells, have also been implicated in the maintenance of HIV infection.These cells, like T cells, are targets for viral replication, where thelevel of viral replication is dependent upon the activation state of thecells. [See Rosenberg et al., The Immunopathogenesis of HIV Infection,Advances in Immunology, Vol. 57, 1989]. Monokines, such as TNF, havebeen shown to activate HIV replication in monocytes and/or macrophages[See Poli et al., Proc. Natl. Acad. Sci., 87:782-784, 1990], therefore,inhibition of monokine production or activity aids in limiting HIVprogression as stated above for T cells.

TNF has also been implicated in various roles with other viralinfections, such as the cytomegalovirus (CMV), influenza virus,adenovirus, and the herpes virus for similar reasons as those noted. TNFis also associated with yeast and fungal infections. SpecificallyCandida albicans has been shown to induce TNF production in vitro inhuman monocytes and natural killer cells. [See Riipi et al., Infectionand Immunity, 58(9):2750-54, 1990; and Jafari et al., Journal ofInfectious Diseases, 164:389-95, 1991. See also Wasan et al.,Antimicrobial Agents and Chemotherapy, 35(10):2046-48, 1991; and Luke etal., Journal of Infectious Diseases, 162:211-214, 1990].

SUMMARY OF THE INVENTION

This invention relates to certain compounds of Formula I ##STR2##wherein R₁ is OH or an ether or ester thereof,

X is YR₂, halogen, nitro, NR₄ R₅ or formyl amine;

Y is O or S(O)_(m), where m is 0, 1 or 2;

R₂ is methyl or ethyl, where either methyl or ethyl may be optionallysubstituted by 1 or more halogens;

R₃ is hydrogen, halogen, C₁₋₄ alkyl, CH₂ NHC(O)C(O)NH₂, halo-substitutedC₁₋₄ alkyl, --CH═CHR_(8'),R₈, cyclopropl optionally subsituted byR_(8'), CN, OR₈, CH₂ OR₈, NR₈ R₁₀, CH₂ NR₈ R₁₀, C(Z')H, C(O)OR₈, C(O)NR₈R₁₀, or --C.tbd.CR_(8') ;

R₄ and R₅ are independently hydrogen or C₁₋₂ alkyl;

R₇ is --(CR₄ R₅)_(q) R₁₂ or C₁₋₆ alkyl wherein the R₁₂ or C₁₋₆ alkylgroup is optionally substituted one or more times by C₁₋₂ alkyloptionally substituted by one to three groups selected from --F, --Br,--Cl, --NO₂, --NR₁₀ R₁₁, --C(═O)R₈, --C(═O)OR₈, --OR₈, --CN, --C(═O)NR₁₀R₁₁, --OC(═O)NR₁₀ R₁₁, --OC(═O)R₈, --NR₁₀ C(═O)NR₁₀ R₁₁, --NR₁₀C(═O)R₁₁, --NR₁₀ C(═O)OR₉, --NR₁₀ C(═O)R₁₃, --C(═NR₁₀)NR₁₀ R₁₁,--C(═N--CN)NR₁₀ R₁₁, --C(═N--CN)SR₉, --NR₁₀ C(═N--CN)NR₁₀ R₁₁, --NR₁₀S(═O)₂ R₉, --S(O)_(m') R₉, --NR₁₀ C(═O)C(═O)NR₁₀ R₁₁, --NR₁₀C(═O)C(═O)R₁₀, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl ortetrazolyl;

R₈ is --H or R₉ ;

R_(8') is R₈ or fluorine;

R₉ is C₁₋₄ alkyl optionally substituted by one to three --F;

R₁₀ is OR₈, hydrogen, or C₁₋₄ alkyl optionally substituted by one tothree fluorines;

R₁₁ is --H or C₁₋₄ alkyl optionally substituted by one to three --F; orwhen R₁₀ and R₁₁ are as NR₁₀ R₁₁ they may together with the nitrogenform a 5 to 7 membered ring optionally containing at least oneadditional heteroatom selected from O, N or S;

R₁₂ is C₃₋₇ cycloalkyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl,pyrazolyl, 1-imidazolyl, 2-imidazolyl, thiazolyl, triazolyl, pyrrolyl,piperazinyl, piperidinyl, morpholinyl, furanyl, 2-thienyl, 3-thienyl,4-thiazolyl, 5-thiazolyl, quinolinyl, naphthyl or phenyl;

R₁₃ is a heterocyclic ring selected from oxazolidinyl, oxazolyl,thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl,thiazolidinyl, isoxazolyl, oxadiazolyl or thiadiazolyl, where R₁₃ isappended to a compound of Formula (I) through a carbon atom of theheterocyclic ring, and where each heterocyclic ring may be unsubstitutedor substituted by one or two C₁₋₂ alkyl groups;

R₁₄ is H or R₇, or when R₁₀ and R₁₄ are as NR₁₀ R₁₄, they may togetherwith the nitrogen atom form a 5 to 7 membered ring optionally containingat least one additional heteroatom selected from O, N or S;

m' is 0, 1 or 2;

q is 0, 1 or 2.

Y' is O or S;

Z is C(═Y')R₁₄, C(═O)OR₁₄, C(═Y')NR₁₀ R₁₄, C(═NR₁₀)NR₁₀ R₁₄, CN,C(═NOR₈)R₁₄, C(═O)NR₈ NR₈ C(═O)R₈, C(═O)NR₈ NR ₁₀ R₁₄, C(═NOR₁₄)R₈,C(═NR₈)NR₁₀ R₁₄, C(═NR₁₄)NR₈ R₈, C(═N--CN)NR₁₀ R₁₄, C(═N--CN)SR₉,2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyrazolyl, 4-pyrazolyl,5-pyrazolyl, 4-triazolyl[1,2,3], 5-triazolyl[1,2,3], 3-triazolyl[1,2,4],5-triazolyl[1,2,4], 5-tetrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-oxadiazolyl[1,2,4],5-oxadiazolyl[1,2,4], 2-oxadiazolyl[1,3,4], 2-thiadiazolyl[1,3,4],2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolidinyl, 4-oxazolidinyl,5-oxazolidinyl, 2-thiazolidinyl, 4-thiazolidinyl or 5-thiazolidinyl,2-imidazolidinyl, 4-imidazolidinyl, or 5-imidazolidinyl; wherein all ofthe heterocyclic ring systems may be optionally substituted one or moretimes by R₁₄ ;

Z' is O, NR₉, NOR₈, NCN, C(--CN)₂, CR₈ CN, CR₈ NO₂, CR₈ C(O)OR₈, CR₈C(O)NR₈ R₈, C(--CN)NO₂, C(--CN)C(O)OR₉, or C(--CN)C(O)NR₈ R₈ ; or

a pharmaceutically acceptable salt thereof.

This invention also relates to pharmaceutical compositions comprising acompound of Formula (I) and a pharmaceutically acceptable excipient.

This invention also relates to a method of mediation or inhibition ofthe enzymatic activity (or catalytic activity) of PDE IV in mammals,including humans, which comprises administering to a mammal in needthereof an effective amount of a compound of Formula (I) or apharmaceutically acceptable salt thereof.

This invention also relates to a method for the treatment of allergicand inflammatory disease which comprises administering to a mammal,including humans, in need thereof, an effective amount of a compound ofFormula (I) or a pharmaceutically acceptable salt thereof.

This invention also relates to a method for the treatment of asthmawhich comprises administering to a mammal, including humans, in needthereof, an effective amount of a compound of Formula (I) or apharmaceutically acceptable salt thereof.

This invention further relates to a method of inhibiting TNF productionin a mammal, including humans, which comprises administering to a mammalin need of such treatment, an effective TNF inhibiting amount of acompound of Formula (I) or a pharmaceutically acceptable salt thereof.This method may be used for the prophylactic treatment or prevention ofcertain TNF mediated disease states effected thereby.

This invention further relates to a method of treating a human afflictedwith a human immunodeficiency virus (HIV), which method comprisesadministering to a human in need of such treatment, an effective amountof a compound of Formula (I) or a pharmaceutically acceptable saltthereof.

Compounds of Formula (I) are useful in the treatment of additional viralinfections, where such viruses are sensitive to upregulation by TNF, orwill elicit TNF production in vivo.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

As used herein, the following terms and expressions have the indicatedmeaning.

"Aryl" or "aralkyl", unless specified otherwise, means an aromatic ringor ring system of 6-10 carbon atoms, such as phenyl, benzyl, phenethyl,or naphthyl. The alkyl chain is meant to include both straight orbranched chain radicals of 1 to 4 carbon atoms.

The term "C₁₋₂ alkyl", "C₁₋₄ alkyl", "C₁₋₆ alkyl" or "alkyl groups"includes both straight or branched chain radicals of 1 to 10 carbonatoms, unless the chain length is otherwise limited thereto, including,but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, and the like.

The term "C₃₋₇ cycloalkyl" means groups of 3-7 carbon atoms, such ascyclopropyl, cyclopropylmethyl, cyclopentyl, or cyclohexyl.

"Cytokine" means any secreted polypeptide that affects the functions ofcells, and is a molecule which modulates interactions between cells inimmune, inflammatory, or hematopoietic responses. A cytokine includes,but is not limited to, monokines and lymphokines regardless of whichcells produce them. The cytokine inhibited by the present invention foruse in the treatment of an HIV-infected human must be a cytokine whichis implicated in (a) the initiation and/or maintenance of T cellactivation and/or activated T cell-mediated HIV gene expression and/orreplication, and/or (b) any cytokine-mediated disease associated problemsuch as cachexia or muscle degeneration.

"Halo" includes all halogen radicals, i.e., chloro, fluoro, bromo, oriodo.

"Heteroaryl" means an aromatic ring system containing one or moreheteroatoms, such as imidazolyl, triazolyl, oxazolyl, pyridyl,pyrimidyl, pyrazolyl, pyrrolyl, furanyl, or thienyl.

"Inhibiting the production of IL-1" or "inhibiting the production ofTNF" means:

a) a decrease of excessive in vivo IL-1 or TNF levels in a human, tonormal levels or below normal levels by inhibition of the in vivorelease of IL-1 by all cells, including but not limited to monocytes ormacrophages;

b) a down regulation, at the translational or transcriptional level, ofexcessive in vivo IL-1 or TNF levels in a human, to normal levels orbelow normal levels; or

c) a down regulation, by inhibition of the direct synthesis of IL-1 orTNF levels as a postranslational event.

"Percentage" and "%" refers to percentage by weight of a component oringredient based on the weight of the total composition containing suchcomponent or ingredient.

"TNF mediated disease or disease states" means any and all diseasestates in which TNF plays a role, either by production of TNF itself, orby TNF causing another cytokine to be released, such as but not limitedto IL-1 or IL-6. A disease state in which IL-1, for instance, is a majorcomponent, and whose production or action is exacerbated or secreted inresponse to TNF, would therefore be considered a disease state mediatedby TNF. As TNF-β (also known as lymphotoxin) has close structuralhomology with TNF-α (also known as cachectin), and since each inducessimilar biologic responses and binds to the same cellular receptor, bothTNF-α and TNF-β are inhibited by the compounds of the present inventionand thus are herein referred to collectively as "TNF" unlessspecifically delineated otherwise.

This invention relates to a method for mediating or inhibiting theenzymatic activity or catalytic activity of PDE IV in a mammal in needthereof and for inhibiting the production of TNF in a mammal in needthereof, which comprises administering to said mammal an effectiveamount of a compound of Formula (I) or a pharmaceutically acceptablesalt thereof.

PDE IV inhibitors are useful in the treatment of a variety of allergicand inflammatory diseases, including: asthma, chronic bronchitis, atopicdermatitis, urticaria, allergic rhinitis, allergic conjunctivitis,vernal conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoidarthritis, septic shock, ulcerative colitis, Crohn's disease,reperfusion injury of the myocardium and brain, chronicglomerulonephritis, endotoxic shock and adult respiratory distresssyndrome. In addition, PDE IV inhibitors are useful in the treatment ofdiabetes insipidus and central nervous system disorders such asdepression and multi-infarct dementia

The viruses contemplated for treatment herein are those that produce TNFas a result of infection, or those which are sensitive to inhibition,such as by decreased replication, directly or indirectly, by the TNFinhibitors of Formula (I). Such viruses include, but are not limited toHIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus andthe Herpes group of viruses, such as, but not limited to, Herpes zosterand Herpes simplex.

This invention more specifically relates to a method of treating amammal, afflicted with a human immunodeficiency virus (HIV), whichcomprises administering to such mammal an effective TNF inhibitingamount of a compound of Formula (I) or a pharmaceutically acceptablesalt thereof.

The compounds of this invention may also be used in association with theveterinary treatment of animals, other than humans, in need ofinhibition of TNF production. TNF mediated diseases for treatment,therapeutically or prophylactically, in animals include disease statessuch as those noted above, but in particular viral infections. Examplesof such viruses include, but are not limited to feline immunodeficiencyvirus (FIV) or other retroviral infection such as equine infectiousanemia virus, caprine arthritis virus, visna virus, maedi virus andother lentiviruses.

The compounds of this invention are also useful in treating yeast andfungal infections, where such yeast and fungi are sensitive toupregulation by TNF or will elicit TNF production in vivo. A preferreddisease state for treatment is fungal meningitis. Additionally, acompound of Formula (I) may be administered in conjunction with otherdrugs of choice for systemic yeast and fungal infections. Drugs ofchoice for fungal infections, include but are not limited to the classof compounds called the polymycins, such as Polymycin B, the class ofcompounds called the imidazoles, such as clotrimazole, econazole,miconazole, and ketoconazole; the class of compounds called thetriazoles, such as fluconazole, and itranazole, and the class ofcompounds called the Amphotericins, in particular Amphotericin B andliposomal Amphotericin B.

A compound of Formula (I) may also be used for inhibiting and/orreducing the toxicity of an anti-fungal, anti-bacterial or anti-viralagent by administering an effective amount of a compound of Formula (I)to a mammal in need of such treatment. Preferably, a compound of Formula(I) is administered for inhibiting or reducing the toxicity of theAmphotericin class of compounds, in particular Amphotericin B.

Preferred Compounds

The preferred compounds of this invention are those where R₁ is OH or--OCOH, X is YR₂ particularly where Y is O and R₂ is methyl substitutedby 1 or more halogens; R₃ is CN or --C.tbd.CH and Z is a carboxylic acidderivative such as a --C(O)OH, a salt thereof or an ester or amidederivative such as C(═Y')R₁₄, C(═O)OR₁₄, C(═Y')NR₁₀ R₁₄, C(═NR₁₀)NR₁₀R₁₄. In addition, it is preferred that the R₃ group be axial and the Zgroup be equatorial.

The specific compounds disclosed herein are:

cis-{4-cyano-4-[3-(cis-3-hydroxycyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylicacid};

cis-{-4-cyano-4-[3-(cis-3-formyloxycyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylicacid}, and

cis-{-4-cyano-4-[3-(trans-3-hydroxycyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylicacid}.

Syntheses

Preparation of the compounds of Formula (I) can be carried out by one ofskill in the art according to the procedures outlined reaction schemeset forth below and the specific chemistries set out in the Examples,infra. While the scheme and the examples illustrate the preparation ofthe cis/cis isomer(s), the cis/trans isomer(s) can be prepared by thesame set of chemistries, with a nominal change in the treatment ofcompound 4; saponifying compound 4 provides the cis/trans compoundnamely thecis-{-4-cyano-4-[3-(trans-3-hydroxycyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylicacid} or the corresponding compounds as defined by Formula I. Thepreparation of any remaining compounds of the Formula (I) not describedtherein may be prepared by the analogous processes disclosed hereinwhich comprise: ##STR3##

EXAMPLE 1

Preparation ofcis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid]

1(a) (3-Cyclopentyloxy-4-methoxyphenyl)acetonitrile

To a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (20 g, 90.8mmol) in acetonitrile (100 mL) was added lithium bromide (15 g, 173mmol) followed by the dropwise addition of trimethylsilylchloride (17.4mL, 137 mmol). After 15 min, the reaction mixture was cooled to 0° C.,1,1,3,3-tetramethyldisiloxane (26.7 mL, 151 mmol) was added dropwise andthe resulting mixture was allowed to warm to room temperature. Afterstirring for 3 h, the mixture was separated into two layers. The lowerlayer was removed, diluted with methylene chloride and filtered throughCelite®. The filtrate was concentrated under reduced pressure, dissolvedin methylene chloride and refiltered. The solvent was removed in vacuoto provide a light tan oil. To a solution of this crudea-bromo-3-cyclopentyloxy-4-methoxytoluene in dimethylformamide (160 mL)under an argon atmosphere was added sodium cyanide (10.1 g, 206 mmol)and the resulting mixture was stirred at room temperature for 18 h, thenpoured into cold water (600 mL) and extracted three times with ether.The organic extract was washed three times with water, once with brineand was dried (K₂ CO₃). The solvent was removed in vacuo and the residuewas purified by flash chromatography (silica gel, 10% ethylacetate/hexanes) to provide an off-white solid (m.p. 32-34° C.); anadditional quantity of slightly impure material also was isolated.

1(b) Dimethyl 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)pimelate

To a solution of (3-cyclopentyloxy-4-methoxyphenyl)acetonitrile (7 g,30.3 mmol) in acetonitrile (200 mL) under an argon atmosphere was addeda 40% solution of Triton-B in methanol (1.4 mL, 3.03 mmol) and themixture was heated to reflux. Methyl acrylate (27 mL, 303 mmol) wasadded carefully, the reaction mixture was maintained at reflux for 5 hand then cooled. The mixture was diluted with ether, was washed oncewith 1N hydrochloric acid and once with brine, was dried (MgSO₄) and thesolvent was removed in vacuo. The solid residue was triturated with 5%ethanol/hexane to provide a white solid (m.p. 81-82° C.); an additionalquantity was also obtained from the filtrate. Anal. (C₂₂ H₂₉ NO₆) calcd:C 65.49, H 7.25, N 3.47. found: C 65.47, H 7.11, N 3.49.

1(c)2-Carbomethoxy-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one

To a suspension of sodium methoxide (350 mL, 1.55 mol, 25% w/w inmethanol) in toluene (2.45 L) heated to 80° C. under a nitrogenatmosphere was added a solution of dimethyl4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)pimelate (350.0 g, 0.87 mol)in toluene (1.05 L) over 10 min. The reaction was heated to 85° C. bydistilling away 250 mL of solvent and was vigorously stirred undernitrogen for 2 hours. The reaction was cooled to 50° C. and was quenchedwith 3N (aq) HCl (700 mL, 2.1 mol). The organic layer was isolated, waswashed once with deionized water (700 mL) and once with brine (700 mL).The organic layer was concentrated via low vacuum distillation to affordcrude2-carbomethoxy-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-onein toluene. This was dissolved in 4.2 L of dimethyl sulfoxide and usedin the next step.

1(d) 4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one

To a suspension of sodium chloride (315 g, 5.39 mol) and deionized water(315 mL) was added the dimethyl sulfoxide (4.2 L) solution of2-carbomethoxy-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-one(323 g, 0.87 mol) and the resulting suspension was heated to 155° C. for1.75 h. The reaction was cooled to 40° C., was quenched into 8 L of icedwater (2° C.) and was extracted with ethyl acetate (3.5 L). The aqueouslayer was isolated and re-extracted with 2.5 L of ethyl acetate. Thecombined organic extract (6 L) was washed two times with deionized water(2×1 L) and once with brine (1 L). The organic layer was isolated andconcentrated in vacuo to afford a residue. This residue was dissolved inrefluxing isopropanol (500 mL), was cooled to 0° C. and held at thistemperature for 1 hour. The crystals were isolated by filtration, werewashed with 250 mL of isopropanol (0° C.), and were dried in a vacuumoven (45° C. at 20 inches) to produce4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one. m.p.111-112° C.; Anal. (C₁₉ H₂₃ NO₃) calcd: C 72.82, H 7.40, N 4.47; found:C 72.72, H 7.39, N 4.48.

1(e)2-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexylidene]-1,3-dithiane

To a solution of 2-trimethylsilyl-1,3-dithiane (9.25 mL, 48.7 mmol) indry tetrahydrofuran (80 mL) at 0° C. under an argon atmosphere was addedrapidly n-butyllithium (2.5M in hexanes, 19.2 mL, 48 mmol). After 10min, the mixture was cooled to -78° C. and a solution of4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one (7.53 g, 23mmol) in tetrahydrofuran (40 mL) was added. After 10 min, aqueous sodiumchloride was added, the mixture was allowed to warm to room temperatureand was diluted with water. This mixture was combined with the productof three substantially similar reactions conducted on ketone (3.04, 6.01and 6.1 g, 48.3 mmol total), the combined mixture was extracted threetimes with methylene chloride, the extract was dried (MgSO₄) andevaporated. Purification by flash chromatography (silica gel, 10% ethylacetate/hexanes) provided a white solid. m.p. 115-116° C.

1(f)cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid]

To a suspension of2-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexylidene]-1,3-dithiane(140.0 g, 0.34 mol) in acetonitrile (500 mL) and deioinized water (140ml) under nitrogen was added trifluoroacetic acid (136 g, 1.19 mol). Thesuspension was heated to 65° C. for 1.25 h followed by the addition of20% sodium hydroxide (420 g, 2.1 mol). The solution was heated at 70 to75° C. for an additional 1.25 h, was cooled to 45° C., deionized water(420 ml)was added followed by 3N (aq) HCl (392 mL, 1.18 mol). Thesuspension was cooled to 5° C. and held for 1 h. The suspension wasfiltered, was washed with cold (5° C.) deionized water (200 mL), and wasdried in a vacuum oven (40° C. at 20 inches) to obtain crudecis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid]. This material was assayed at 98.5% and was found to a 98.8:1.2mixture of cis-to-trans isomers, which was contaminated with 0.1% ofresidual 1,3-propanedithiol. This material was purified via an oxidativeworkup as follows.

To a hot solution (65° C.) of crudecis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid] (85 g, 0.247 mol) in acetonitrile (425 mL) was added 1M sodiumhydroxide (425 mL, 0.425 mol). To the solution (60° C.) was added 4.25 gof calcium hypochlorite and the suspension was vigorously stirred for 2h. The reaction was concentrated by distilling out 320 mL of solvent,followed by the addition of ethyl acetate (425 mL). The reaction wasagain concentrated by distilling out 445 mL of solvent, was cooled to55° C. followed by the addition of ethyl acetate (1.0 L) and 6N (aq.)HCl (100 mL). The organic layer was isolated, was washed three timeswith deionized water (3×300 mL), was filtered and was concentrated bydistilling out 530 mL of solvent. To the solution was added ethylacetate (635 mL) with continued distillation to remove 750 mL ofsolvent. The solution was cooled to 65° C. followed by the addition ofhexane (340 mL). The suspension was cooled to 5° C., held at thistemperature for 1 hour, was filtered and was washed with cold (5° C.)10% ethyl acetate/hexane (200 mL). The solid was collected and was driedin a vacuum oven (40° C. at 20 inches) to obtaincis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid]. This material was found to contain no trans isomer. Anal.(C₂₀ H₂₅NO₄) calcd: C 69.95, H 7.34, N 4.08; found: C 69.90, H 7.35, N 4.02.

EXAMPLE 2

Preparation ofcis-{4-cyano-4-[3-(trans-3-hydroxycyclopentyloxy)-4-methoxyphenyl]-cyclohexane-1-carboxylicacid}

2(a) cis-[4-Cyano-4-(3-hydroxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid]

To a solution of boron tribromide in dichlorormethane (0.1M, 335 mL,33.5 mmol) under an argon atmosphere at -78° C. was slowly added asolution ofcis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid] (4.03 g, 11.7 mmol) in dichloromethane (180 mL). The mixture wasstirred for 5 min, 15% sodium methoxide in methanol was added to pH 8-9and the reaction was warmed to RT. Water (100 mL) was added and themixture was acidified with 3N aqueous hydrochloric acid to pH 1-2. Theorganic layer was separated, was dried (MgSO₄ /Na₂ SO₄), was filteredand was evaporated. The residue was twice dissolved in chloroform andthe solution was evaporated to yield a white solid. ¹ H NMR(400 MHz,CDCl.sub.₃) δ 7.01 (d, J=2.4 Hz, 1H), 6.96 (d of d, J=2.4, 8.5 Hz, 1H),3.89 (s, 3H), 2.31 (m, 1H), 2.21 (br t, J=13.6 Hz, 4H), 1.98 (m,2H),1.77 (m, 2H); mp 190-193° C.

2(b) Methylcis-[-4-cyano-4-(3-hydroxy-4-methoxyphenyl)cyclohexane-1-carboxylate]

p-Toluenesulfonic acid monohydrate (0.015 g, 0.08 mmol) was added to asolution of the compound of Example 2(a) (0.70 g, 2.54 mmol) in drymethanol (20 mL) under an argon atmosphere and the reaction was stirredfor 6 h at 45-50° C. The reaction was cooled to RT and was stirred foran additional 16 h. The solution was evaporated and the residue waspurified by flash chromatography (silica gel, 50% hexane/ethyl acetate)to yield the title compound as a white solid. ¹ H NMR(400 MHz, CDCl₃) δ7.01 (m, 2H), 6.85 (d, J=9.1 Hz, 1H), 3.90 (s, 3H), 3.72 (s, 3H), 2.35(t of t, J=3.6, 12.2 Hz, 1H), 2.14-2.25 (m, 4H), 2.00 (app q, J=13.4 Hz,1H), 1.99 (app q, J=13.4 Hz, 1H), 1.77 (app t, J=13.4 Hz, 1H), 1.76 (appt, J=13.4 Hz, 1H); mp 106-107° C.

2(c) Methylcis-{-4-cyano-4-[3-(trans-3-hydroxycyclopentyloxy)-4-methoxyphenyl]-cyclohexane-1-carboxylate}

The compound of Example 2(b) (0.69 g, 2.37 mmol) was dissolved intetrahydrofuran (20 mL) under an argon atmosphere and was treated withtriphenylphosphine (1.24 g, 4.74 mmol) and cis-1,3-cyclopentanediol(0.49 g, 4.74 mmol). Diethyl azodicarboxylate (0.83 g, 4.74 mmol) wasadded and the mixture was stirred at RT for 16 h. The solution wasevaporated, the residue was diluted with ether and the white solid wasremoved by filtration. The filtrate was concentrated and the residue waspurified by flash chromatography (silica gel, 50% hexane/ethyl acetate)to yield a mixture of the title compound and triphenylphosphine oxide.The mixture was diluted with ether and the white solidtriphenylphosphine oxide was removed by filtration. Evaporation of thefiltrate yielded the tide compound as a sticky, colorless semi-solid. ¹H NMR(400 MHz, CDCl.sub.₃) δ 7.07 (d, J=2.4 Hz, 1H), 7.02 (d of d,J=2.4, 8.8 Hz, 1H), 6.87 (d, J=8.8 Hz, 1H), 4.99 (m, 1H), 4.37 (m, 1H),3.85 (s, 3H), 3.74 (s, 3H), 3.16 (d, J=9.1 Hz, 1H), 2.39 (m, 1H),1.88-2.25 (m, 12H), 1.80 (br t, J=13.5 Hz, 2H).

2(d)cis-{-4-cyano-4-[3-(trans-3-hydroxycyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylicacid}

The compound of Example 2(c) (0.10 g, 0.27 mmol) was dissolved in 5:5:2tetrahydrofuran/methanol/water (5 mL), sodium hydroxide (0.035 g, 0.88mmol) was added and the mixture was stirred at RT for 3 h. The solventwas evaporated, the residue was partitioned between 5% aqueous NaOH anddichloromethane and the layers were separated. The aqueous layer wasacidified to pH 3 with 3N aqueous hydrochloric acid and was extractedthree times with 5% methanol in chloroform. The organic extracts werecombined, were dried (MgSO4), filtered and evaporated. The residue waspurified by flash chromatography (silica gel, 90:10:1chloroform/methanol/water) to yield a solid which was slurried in ether,was collected by filtration and was dried in vacuo to afford the titlecompound. MS(CI/NH₃) m/e 377 [M+NH_(3]+;) ¹ H NMR(400 MHz, CDCl₃) δ 7.08(br s, 1H), 7.03 (br d, J=8.5Hz, 1H), 6.88 (d, J=8.5 Hz, 1H), 4.98 (m,1H), 4.38 (m, 1H), 3.84 (s, 1H), 2.41 (m, 1H), 1.77-2.29 (m, 16H); Anal.(C₂₀ H₂₅ NO₅ ·0.9 H₂ O) calcd: C, 63.95; H,7.19; N,3.73. found: C,64.06; H, 6.88; N, 3.77; mp 161-163° C.

EXAMPLE 3

Preparation ofcis-{4-cyano-4-[3-(cis-3-hydroxycyclopentyloxy)-4-methoxyphenyl]-cyclohexane-1-carboxylicacid}

3(a) Methylcis-{-4-cyano-4-[3-(cis-3-formyloxycyclopentyloxy)-4-methoxyphenyl]-cyclohexane-1-carboxylate}

The compound of Example 2(c) (0.68 g, 1.83 mmol) was dissolved intetrahyrofuran (20 mL) under an argon atmosphere and was treated withtriphenylphosphine (0.96 g, 3.66 mmol) and formic acid (0.17 g, 3.66mmol). Diethyl azodicarboxylate (0.64 g, 3.66 mmol) was added and themixture was stirred at RT for 16 h. The solution was evaporated, etherwas added and the white solid was removed by filtration. The filtratewas concentrated and the residue was purified by flash chromatography(silica gel, 65% hexane/ethyl acetate) to yield the title compound as aclear colorless oil. ¹ H NMR(400 MHz, CDCl₃) δ 8.02 (s,1H), 7.0 (d of d,J=2.4, 8.2 Hz, 1H), 6.99 (d, J=2.4 Hz, 1 H), 6.87 (d, J=8.2 Hz, 1H),5.48 (m, 1H), 4.95 (m, 1H), 3.84 (s, 3H), 3.72 (s, 3H), 2.31-2.40 (m,2H), 2.13-2.28 (m, 7H), 1.96-2.06 (m, 3H), 1.74-1.87 (m, 3H).

3(b)cis-{-4-cyano-4-[3-(cis-3-hydroxycyclopentyloxy)-4methoxyphenyl]cyclohexane-1-carboxylicacid}

The compound of Example 3(a) (0.52 g, 1.31 mmol) was dissolved in 5:5:2tetrahydrofuran/methanol/water (20mL), sodium hydroxide (0.32 g, 8.0mmol) was added and the mixture was stirred at RT for 2.5 h. The solventwas evaporated and the aqueous residue was acidified to pH 1-2 with 3Naqueous hydrochloric acid. The white solid product was collected, waswashed with water and was dried in vacuo to afford the title compound asa white solid. MS(CI/NH₃) m/e 377 [M+NH3]+; 1H NMR(250 MHz, CDC1₃) δ6.98 (m, 2H), 6.86 (d, J=8.2 Hz, 1H), 4.97 (m, 1H), 4.59 (m, 1H), 3.85(s, 3H), 1.64-2.47 (m, 17H); mp 143-145° C.

METHODS OF TREATMENT

In order to use a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof may be used neat though a preferred technique isto present them with a carrier/diluent accordance with standardpharmaceutical practice. Any formulation compatible with the chosenmethod of delivery and the stability of the compound may be used. Oneskilled in the art will be able to select and prepare an acceptableformulation in accordance with standard practices in the field of theformulary arts.

The compounds of Formula (I) or may be administered orally (when activeby this route), oral, intravenous, intraperitoneal, and intramuscularadministration, topically, parenterally, or by inhalation inconventional dosage forms prepared by combining such agent with standardpharmaceutical carriers according to conventional procedures in anamount sufficient to produce the desired therapeutic activity.

The amount of a compound of Formula (I) required for therapeutic effecton topical administration will, of course, vary with the compoundchosen, the nature and severity of the condition and the animalundergoing treatment, and is ultimately at the discretion of thephysician.

The daily dosage regimen for oral administration is suitably about 0.001mg/kg to 100 mg/kg, preferably 0.01 mg/Kg to 40 mg/Kg, of a compound ofFormula (I) or a pharmaceutically acceptable salt thereof calculated asthe free base. The active ingredient may be administered from 1 to 6times a day, sufficient to exhibit activity.

UTILITY EXAMPLES Example A

Inhibitory effect of compounds of Formula (I) on in vitro TNF productionby human monocytes

The inhibitory effect of compounds of Formula (I) on in vitro TNFproduction by human monocytes may be determined by the protocol asdescribed in Badger et al., EPO published Application 0 411 754 A2, Feb.6, 1991, and in Hanna, WO 90/15534, Dec. 27, 1990.

Example B

Two models of endotoxic shock have been utilized to determine in vivoTNF activity for the compounds of Formula (I). The protocol used inthese models is described in Badger et al., EPO published Application 0411 754 A2, Feb. 6, 1991, and in Hanna, WO 90/15534, Dec. 27, 1990.

The exemplified compounds herein demonstrated a positive in vivoresponse in reducing serum levels of TNF induced by the injection ofendotoxin.

Example C

Isolation of PDE Isozymes

The phosphodiesterase inhibitory activity and selectivity of thecompounds of Formula (I) can be determined using a battery of fivedistinct PDE isozymes. The tissues used as sources of the differentisozymes are as follows: 1) PDE Ib, porcine aorta; 2) PDE Ic, guinea-pigheart; 3) PDE III, guinea-pig heart; 4) PDE IV, human monocyte; and 5)PDE V (also called "Ia"), canine trachealis. PDEs Ia, Ib, Ic and III arepartially purified using standard chromatographic techniques [Torphy andCieslinski, Mol. Pharmacol., 37:206-214, 1990]. PDE IV is purified tokinetic homogeneity by the sequential use of anion-exchange followed byheparin-Sepharose chromatography [Torphy et al., J. Biol. Chem.,267:1798-1804, 1992].

Phosphodiesterase activity is assayed as described in the protocol ofTorphy and Cieslinski, Mol. Pharmacol., 37:206-214, 1990. Positive IC₅₀'s in the nanomolar to μM range for compounds of the workings examplesdescribed herein for Formula (I) have been demonstrated.

Example D

The ability of selected PDE IV inhibitors to increase cAMP accumulationin intact tissues is assessed using U-937 cells, a human monocyte cellline that has been shown to contain a large amount of PDE IV. To assessthe activity of PDE IV inhibition in intact cells, nondifferentiatedU-937 cells (approximately 10⁵ cells/reaction tube) were incubated withvarious concentrations (0.01-1000 μM) of PDE inhibitors for one minuteand 1 μM prostaglandin E2 for an additional four minutes. Five minutesafter initiating the reaction, cells were lysed by the addition of 17.5%perchloric acid, the pH was neutralized by the addition of 1 M potassiumcarbonate and cAMP content was assessed by RIA. A general protocol forthis assay is described in Brooker et al., Radioimmunassay of cyclic AMPand cyclic GMP., Adv. Cyclic Nucleotide Res., 10:1-33, 1979. Thecompounds of the working examples as described herein for Formula (I)have demonstrated a positive EC₅₀ s in the μM range in the above assay.

No toxic effects are expected when these compounds are administered inaccordance with the present invention.

What is claimed is:
 1. A compound of Formula I ##STR4## wherein R₁ is OHor an ether or ester thereof,X is YR₂, halogen, nitro, NR₄ R₅ or formylamine; Y is O or S(O)_(m), where m is 0, 1 or 2; R₂ is methyl or ethyl,where either methyl or ethyl may be optionally substituted by 1 or morehalogens; R₃ is hydrogen, halogen, C₁₋₄ alkyl, CH₂ NHC(O)C(O)NH₂,halo-substituted C₁₋₄ alkyl, --CH═CHR_(8') R_(8'), cyclopropl optionallysubsituted by R_(8'), CN, OR₈, CH₂ OR₈, NR₈ R₁₀, CH₂ NR₈ R₁₀, C(Z')H,C(O)OR₈, C(O)NR₈ R₁₀, or --C.tbd.CR_(8') ; R₄ and R₅ are independentlyhydrogen or C₁₋₂ alkyl; R₇ is --(CR₄ R₅)_(q) R₁₂ or C₁₋₆ alkyl whereinthe R₁₂ or C₁₋₆ alkyl group is optionally substituted one or more timesby C₁₋₂ alkyl optionally substituted by one to three groups selectedfrom --F, --Br, --Cl, --NO₂, --NR₁₀ R₁₁, --C(═O)R₈, --C(≅O)OR₈, --OR₈,--CN, --C(═O)NR₁₀ R₁₁, --OC(═O)NR₁₀ R₁₁, --OC(═O)R₈, --NR₁₀ C(═O)NR₁₀R₁₁, --NR₁₀ C(═O)R₁₁, --NR₁₀ C(═O)OR₉, --NR₁₀ C(═O)R₁₃, --C(═NR₁₀)NR₁₀R₁₁, --C(═N--CN)NR₁₀ R₁₁, --C(═N--CN)SR₉, --NR₁₀ C(═N--CN)NR₁₀ R₁₁,--NR₁₀ S(═O)₂ R₉, --S(O)_(m') R₉, --NR₁₀ C(═O)C(═O)NR₁₀ R₁₁, --NR₁₀C(═O)C(═O)R₁₀, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl ortetrazolyl; R₈ is --H or R₉ ; R_(8') is R₈ or fluorine; R₉ is C₁₋₄ alkyloptionally substituted by one to three --F; R₁₀ is OR₈, hydrogen, orC₁₋₄ alkyl optionally substituted by one to three fluorines; R₁₁ is --Hor C₁₋₄ alkyl optionally substituted by one to three --F; or when R₁₀and R₁₁ are as NR₁₀ R₁₁ they may together with the nitrogen form a 5 to7 membered ring optionally containing at least one additional heteroatomselected from O, N or S; R₁₂ is C₃₋₇ cycloalkyl, 2-pyridyl, 3-pyridyl,4-pyridyl, pyrimidyl, pyrazolyl, 1-imidazolyl, 2-imidazolyl, thiazolyl,triazolyl, pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl,2-thienyl, 3-thienyl, 4-thiazolyl, 5-thiazolyl, quinolinyl, naphthyl orphenyl; R₁₃ is a heterocyclic ring selected from oxazolidinyl, oxazolyl,thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl,thiazolidinyl, isoxazolyl, oxadiazolyl or thiadiazolyl, where R₁₃ isappended to a compound of Formula (I) through a carbon atom of theheterocyclic ring, and where each heterocyclic ring may be unsubstitutedor substituted by one or two C₁₋₂ alkyl groups; R₁₄ is H or R₇, or whenR₁₀ and R₁₄ are as NR₁₀ R₁₄, they may together with the nitrogen atomform a 5 to 7 membered ring optionally containing at least oneadditional heteroatom selected from O, N or S; m' is 0, 1 or 2; q is 0,1 or
 2. Y' is O or S; Z is C(═Y')R₁₄, C(═O)OR₁₄, C(═Y')NR₁₀ R₁₄,C(═NR₁₀)NR₁₀ R₁₄, CN, C(═NOR₈)R₁₄, C(═O)NR₈ NR₈ C(═O)R₈, C(═O)NR₈ NR₁₀R₁₄, C(═NOR₁₄)R₈, C(═NR₈)NR₁₀ R₁₄, C(═NR₁₄)NR₈ R₈, C(═N--CN)NR₁₀ R₁₄,C(═N--CN)SR₉, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyrazolyl,4-pyrazolyl, 5-pyrazolyl, 4-triazolyl[1,2,3], 5-triazolyl[1,2,3],3-triazolyl[1,2,4], 5-triazolyl[1,2,4], 5-tetrazolyl, 2-oxazolyl,4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl,3-oxadiazolyl[1,2,4], 5-oxadiazolyl[1,2,4], 2-oxadiazolyl[1,3,4],2-thiadiazolyl[1,3,4], 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,2-oxazolidinyl, 4-oxazolidinyl, 5-oxazolidinyl, 2-thiazolidinyl,4-thiazolidinyl or 5-thiazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl,or 5-imidazolidinyl; wherein all of the heterocyclic ring systems may beoptionally substituted one or more times by R₁₄ ; Z' is O, NR₉, NOR₈,NCN, C(--CN)₂, CR₈ CN, CR₈ NO₂, CR₈ C(O)OR₈, CR₈ C(O)NR₈ R₈, C(--CN)NO₂,C(--CN)C(O)OR₉, or C(--CN)C(O)NR₈ R₈ ; or a pharmaceutically acceptablesalt thereof.
 2. A compound of claim 1 wherein R₁ is OH or --OCOH, X isYR₂, Y is O, R₂ is methyl substituted by 1 or more halogens; R₃ is CN or--C.tbd.CH, Z is a carboxylic acid derivative such as a --C(O)OH, a saltthereof or an ester or amide derivative such as C(═Y')R₁₄, C(═O)OR₁₄,C(═Y')NR₁₀ R₁₄, C(═NR₁₀)NR₁₀ R₁₄ and the R₃ group is axial and the Zgroup is equatorial.
 3. A compound of claim 2 whichiscis-{4-cyano-4-[3-(cis-3-hydroxycyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylicacid};cis-{-4-cyano-4-[3-(cis-3-formyloxycyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylicacid}, orcis-{-4-cyano-4-[3-(trans-3-hydroxycyclopentyloxy)4-methoxyphenyl]cyclohexane-1-carboxylicacid}, or a pharmaceutically acceptable salt thereof.
 4. A method fortreating asthma comprising a compound according to claim 1 and apharmaceutically acceptable excipient.
 5. A pharmaceutical compositioncomprising a compound of according to claim
 1. 6. A process forpreparing an acid of formula IV ##STR5## wherein R₁ is hydrogen oranother substituent and X is OH or a salt thereof or --O--C₁₋₆ alkyl,which process comprises hydrolyzing a thioketene of formula (C) ##STR6##where R is hydrogen using an acid and aqueous solvent system and heatingthe mixture to between 40 and 80° C. for 30 minutes to 2 hours, and thenadding a base.
 7. The process of claim 6 wherein the base is an alkalimetal alkoxide.
 8. The process of either claim 6 or 7 wherein the acidis trifluoroacetic acid.
 9. The process of any one of claims 6 to 8wherein the product is an acid of formula IV which iscis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid] or a salt thereof.